Synergistic combination

ABSTRACT

The invention relates to the combined administration of PDE inhibitors and β 2  adrenoceptor agonists for the treatment of respiratory tract disorders.

FIELD OF APPLICATION OF THE INVENTION

[0001] The invention relates to the combination of certain known activecompounds for therapeutic purposes.

[0002] The substances used in the combination according to the inventionare known active compounds from the PDE inhibitors class and activecompounds from the β₂ adrenoceptor agonists class. Their combined use inthe sense according to the invention for therapeutic purposes has notyet been described in the prior art.

DESCRIPTION OF THE INVENTION

[0003] It is the object of the present invention to make availablerespiratory tract therapeutics which fulfill the following conditions:

[0004] Good antiinflammatory action

[0005] Marked bronchorelaxation and dilatation

[0006] Good oral availability, at least with respect to the PDEinhibitor

[0007] Minor side effects

[0008] Good suitability for long-term therapy

[0009] Favorable influence on bronchial hyperreactivity.

[0010] It has now been found that the combined use of a PDE inhibitorwhich can be used as a respiratory tract therapeutic and of a β₂adrenoceptor agonist outstandingly fulfills the abovementionedconditions.

[0011] The invention thus relates to the combined use of a PDE inhibitorwhich can be used as a respiratory tract therapeutic and a β₂adrenoceptor agonist in the treatment of respiratory tract disorders.

[0012] PDE inhibitors which can be used as respiratory tracttherapeutics in the sense of the present invention are those compoundswhich slow the breakdown of cyclic AMP (CAMP) or cyclic GMP (cGMP) byinhibition of the phosphodiesterases, which can lead to a relativeincrease in the intracellular concentration of CAMP or cGMP.

[0013] Possible PDE inhibitors within the meaning of the presentinvention are primarily those substances which are to be considered partof the PDE4 inhibitor class and those substances which can be designatedas mixed types of PDE3/4 inhibitors. By way of example, those PDEinhibitors may be mentioned which are described or claimed in thefollowing patent applications and patents: DE 1545687, DE 2028869, DE2123328, DE 2315801, DE 2402908, DE 2413935, DE 3900233, EP 0103497, EP0139464, EP 0158380, EP 0163965, EP 0335386, EP 0389282, EP 0428302, EP0435811, EP 0459505, EP 0470805, EP 0490823, EP 0506194, EP 0511865, EP0527117, EP 0557016, EP 0626939, EP 0664289, EP 0671389, EP 0685474, EP0685475, EP 0685479, EP 0736532, EP 0738715, EP 0748805, EP 0763534, EP0816357, EP 0819688, EP 0819689, EP 0832886, EP 0834508, EP 0848000, JP92234389, JP 94329652, JP 95010875, JP 98072415, JP 98147585, U.S. Pat.No. 5,703,098, U.S. Pat. No. 5,739,144, WO 9117991, WO 9200968, WO9212961, WO 9307146, WO 9315044, WO 9315045, WO 9318024, WO 9319068, WO9319720, WO 9319747, WO 9319749, WO 9319751, WO 9325517, WO 9402465, WO9412461, WO 9420455, WO 9422852, WO 9427947, WO 9501338, WO 9501980, WO9503794, WO 9504045, WO 9504046, WO 9505386, WO 9508534, WO 9509623, WO9509624, WO 9509627, WO 9509836, WO 9514667, WO 9514680, WO 9514681, WO9517392, WO 9517399, WO 9519362, WO 9520578, WO 9522520, WO 9524381, WO9527692, WO 9535281, WO 9535283, WO 9535284, WO 9600218, WO 9601825, WO9606843, WO 9611690, WO 9611917, WO 9612720, WO 9631486, WO 9631487, WO9635683, WO 9636595, WO 9636596, WO 9636611, WO 9636625, WO 9636638, WO9638150, WO 9639408, WO 9640636, WO 9703967, WO 9704779, WO 9705105, WO9708143, WO 9709345, WO 9712895, WO 9718208, WO 9719078, WO 9720833, WO9722585, WO 9722586, WO 9723457, WO 9723460, WO 9723461, WO 9724117, WO9724355, WO 9725312, WO 9728131, WO 9730999, WO 9731000, WO 9732853, WO9735854, WO 9736905, WO 9743288, WO 9744036, WO 9744322, WO 9747604, WO9748697, WO 9804534, WO 9805327, WO 9806692, WO 9806704, WO 9807715, WO9808828, WO 9808830, WO 9808841, WO 9808844, WO 9809946, WO 9809961, WO9811113, WO 9814448, WO 9818796, WO 9821208, WO 9822453, WO 9845268, WO9855481, WO 9856756, WO 9905111, WO 9905112, WO 9505113, WO 9906404 andWO 9918095. Those PDE inhibitors are to be emphasized which are claimedin the patent applications or patents EP 0393500, EP 0510562, EP0553174, WO 9501338, WO 9603399, WO 9636625, WO 9636626, WO 9735854, WO9821208, WO 9831674, WO 9840382, WO 9855481, WO 9905111, WO 9905112, WO9905113, WO 9931071 and WO 9931090. Substances having good oralavailability are preferred here.

[0014] Exemplary PDE inhibitors are shown on the following pages withthe aid of their formulae:

[0015] No hydrogen atoms are indicated in the above formulae. —O isaccordingly —OH, —N is NH₂. Methyl groups, e.g. on the oxygen atoms, areindicated by lines.

[0016] PDE inhibitors to be emphasized which are selected from theabovementioned compounds and which may be mentioned are the activecompounds arofylline, atizoram, AWD-12-281, BAY-19-8004, benafentrine,BYK-33043, CC-3052, CDP-840, CI-1018, cipamfylline, CP-220629,CP-293121, D-22888, D-4396, D-4418, denbufylline, filaminast, GW-3600,ibudilast, KF-17625, KS-506-G, laprafylline, NA-0226A, NA-23063A,ORG-20241, ORG-30029, PDB-093, pentoxifylline, piclamilast, roflumilast,rolipram, RPR-117658, RPR-122818, RPR-132294, RPR-132703, RS-17597,RS-25344-000, SB-207499, SB-210667, SB-211572, SB-211600, SB-212066,SB-212179, SDZ-ISQ-844, SDZ-MNS-949, SKF-107806, SQ-20006, T-2585,T-440, tibenelast, tolafentrine, UCB-29646, V-11294A, YM-58997, YM-976and zardaverine.

[0017] The compounds preferred from the group of the abovementioned PDEinhibitors are arofylline, cipamfylline, D-4418, filaminast, ibudilast,laprafylline, ORG-20241, piclamilast, rolipram, SB-207499, tibenelastand V-11294A. The compounds particularly preferred are BYK-33043 and inparticular roflumilast.

[0018] β₂ adrenoceptor agonists which may particularly be mentioned arethose selectively acting substances which only have a slight cardiacaction and therefore are also employed in therapy, in particular in theoral therapy of respiratory tract disorders. β₂ adrenoceptor agonistswhich may be mentioned are, for example: AR-C68397AA, broxaterol,CHF-1035, HOKU-81, ibuterol, KUL-1248, soterenol, meluadrine, TA-2005,tiaramide, salbutamol, levosalbutamol, tulobuterol, terbutaline,carbuterol, pirbuterol, reproterol, clenbuterol, fenoterol,hexoprenaline, orciprenaline, isoprenaline, formoterol, salmeterol,rimiterol, procaterol, bambuterol, bitolterol and mabuterol. The orallyreadily available β₂ adrenoceptor agonists such as clenbuterol,orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol andreproterol are preferred. Particularly preferred are the so-called longacting β₂ adrenoceptor agonists, such as salmeterol.

[0019] The PDE inhibitors and the β₂ adrenoceptor agonists can bepresent as such or in chemically bonded form. It is understood herebythat the active compounds mentioned can also be present, for example, inthe form of their pharmacologically tolerable salts and/or as solvates(e.g. hydrates), and/or in the form of their N-oxides etc. Suitablepharmacologically tolerable salts here are in particular water-solubleand water-insoluble acid addition salts with acids such as, for example,hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid,sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid,2-(4-hydroxybenzoyl)-benzoic acid, butyric acid, sulfosalicylic acid,maleic acid, lauric acid, malic acid, fumaric acid, succinic acid,oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonicacid, methanesulfonic acid or 1-hydroxy-2-naphthoic acid, the acidsbeing employed in salt preparation—depending on whether it is a mono- orpolybasic acid and depending on which salt is desired—in an equimolarquantitative ratio or one differing therefrom. Furthermore, the activecompounds mentioned can also be present as pure enantiomers or asenantiomer mixtures in any mixing ratio.

[0020] Respiratory tract disorders which may be mentioned are inparticular allergen- and inflammation-induced bronchial disorders(bronchitis, obstructive bronchitis, spastic bronchitis, allergicbronchitis, allergic asthma, bronchial asthma, COPD), which can betreated by the combination according to the invention also in the senseof a long-term therapy (if desired with appropriate adjustment of thedose of the individual components to the needs at the time, for exampleneeds subject to seasonally related variations).

[0021] “Combined use” or “combination” within the meaning of the presentinvention is to be understood as meaning that the individual componentscan be administered simultaneously (in the form of a combinationmedicament), more or less simultaneously (from separate pack units) orin succession (directly in succession or else alternatively at arelatively large time interval) in a manner which is known per se andcustomary.

[0022] Within the meaning of the present invention, “use” is preferablyunderstood as meaning the oral administration of both active compounds.If only the PDE inhibitor is administered orally, “use” with respect tothe β₂ adrenoceptor agonist is understood in particular as meaningtopical application in inhalatory form. For this, the β₂ adrenoceptoragonist is preferably administered by inhalation in the form of anaerosol, the aerosol particles of solid, liquid or mixed compositionhaving a diameter of 0.5 to 10 μm, advantageously of 2 to 6 μm.

[0023] Aerosol generation can be carried out, for example, bypressure-driven jet atomizers or ultrasonic atomizers, butadvantageously by propellant-driven metered aerosols or propellant-freeadministration of micronized active compounds from inhalation capsules.

[0024] The active compounds are dosed in an order of magnitude customaryfor the individual dose, it more likely being possible, on account ofthe individual actions, which are mutually positively influencing andreinforcing, to reduce the respective doses on the combinedadministration of the active compounds compared with the norm.Customarily, the β₂ adrenoceptor agonist (depending on potency) isadministered in a dose of, for example, 0.002 to 2.0 mg per day onadministration by inhalation.

[0025] Depending on the inhaler system used, in addition to the activecompounds the administration forms additionally contain the requiredexcipients, such as, for example, propellants (e.g. Frigen in the caseof metered aerosols), surface-active substances, emulsifiers,stabilizers, preservatives, flavorings, fillers (e.g. lactose in thecase of powder inhalers) or, if appropriate, further active compounds.

[0026] For the purposes of inhalation, a large number of apparatuses areavailable with which aerosols of optimum particle size can be generatedand administered, using an inhalation technique which is as right aspossible for the patient. In addition to the use of adaptors (spacers,expanders) and pear-shaped containers (e.g. Nebulator®, Volumatic®), andautomatic devices emitting a puffer spray (Autohaler®), for meteredaerosols, in particular in the case of powder inhalers, a number oftechnical solutions are available (e.g. Diskhaler®, Rotadisk®,Turbohaler® or the inhaler described in European Patent Application EP 0505 321), using which an optimal administration of active compound canbe achieved.

[0027] In the case of the oral administration of the β₂ adrenoceptoragonists together with the PDE inhibitor, which is the preferredadministration form, the β₂ adrenoceptor agonist is administered in adaily dose of, for example, 0.05 to 60 mg. For the PDE inhibitors, it ispossible in the case of oral administration to vary the doses—dependingon the active compound—within a wide range, it being possible, asbounds, to start from a dose of 1-2000 μg/kg of body weight. In the caseof the administration of the preferred PDE inhibitor roflumilast, thedose is in the range from 2-20 μg/kg of body weight.

[0028] The PDE inhibitors to be administered orally are formulated—ifappropriate together with the β₂ adrenoceptor agonists—to givemedicaments according to processes known per se and familiar to theperson skilled in the art. The pharmacologically active compounds areemployed as medicaments, preferably in combination with suitablepharmaceutical excipients or vehicles, in the form of tablets, coatedtablets, capsules, emulsions, suspensions or solutions, the activecompound content advantageously being between 0.1 and 95% and, by theappropriate choice of the excipients and vehicles, it being possible toachieve a pharmaceutical administration form precisely tailored to theactive compound(s) and/or to the desired onset of action (e.g. asustained-release form or an enteric form). Particulady worthy ofmention within the meaning of the combined, oral administration of bothactive compounds according to the invention are oral administrationforms, e.g. tablets or capsules, in which one part of the β₂adrenoceptor agonist and the PDE inhibitor is present in nonsustained-release form and a further, preferably larger part, of the β₂adrenoceptor agonist is present in sustained-release form.

[0029] The person skilled in the art is familiar on the basis of his/herexpert knowledge with which excipients or vehicles are suitable for thedesired pharmaceutical formulations. In addition to solvents,gel-forming agents, tablet excipients and other active compoundcarriers, it is possible to use, for example, antioxidants, dispersants,emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers,colorants or permeation promoters and complexing agents (e.g.cyclodextrins).

Pharmacology

[0030] Model

[0031] Late Inflammatory Airway Reaction in theOvalbumin-sensitized/-challenged Brown-Norway Rat Anti-inflammatoryactivity of Roflumilast, Pumafentrine (BYK-33043), and Salmeterol wasdetermined in ovalbumin (OVA)-sensitized and OVA-challenged Brown Norwayrats. Sensitization was done by simultaneous injection of Bordetellapertussis suspension i.p. and OVA/AHG suspension s.c. on day 1, 14 and21. 28 days after start of sensitization, conscious Brown-Norway ratswere challenged by inhalation of the aerosolized OVA solution for 1 h(˜20 ml/h). Non-challenged, only sensitized animals were used asbaseline control. The drugs (thoroughly mixed with lactose) or theplacebo control (lactose) were administered intratracheally (i.t.) asdry powders 1 h before OVA-challenge. 48 h later, OVA-challenged ornon-challenged animals were anaesthetized and bronchoalveolar lavage(BAL) was performed using 3×4 ml BAL buffer per animal. The number oftotal cells and eosinophils in the BAL fluid, and the concentration ofprotein in the cell-free BAL fluid were determined. Drug-inducedrelative changes were calculated and statistically analyzed by theJonckheere Terpstra test. Results % Inhibition ofInfiltration/Accumulation [Median/ PDE3/4 Dose Appl. Mean ± SEM]Compound IC50[μmol] [μmol/kg] Route N Total cells EOS ProteinRoflumilast >10/0.0007 0.3 it 8 −25 −15 −8 −37.6 ± 26.7   ^( −22 ± 25.7)−22.3 ± 25.5   Pumafentrine 0.028/0.007 3 it 8 −19 −26 17 −39.1 ± 30.5  −28.5 ± 30.1   23.5 ± 10.6 Salmeterol 3 it 8 19 39 44  6.3 ± 17.9   31 ±14.8 37.5 ± 16.2 Salmeterol/ 3/0.3 it 8 50 67 ** 59 ** Roflumilast 34.5± 21.1   61.1 ± 7.9 **   50.8 ± 13.6 ** Salmeterol/ 3/3 it 8 56 * 85 **75 ** Pumafentrine   58.1 ± 12.3 *    83 ± 3.7 **   67.1 ± 11.1 **

SUMMARY

[0032] The PDE inhibitors Roflumilast (PDE4 inhibitor) and Pumafentrine(PDE3>4 inhibitor) administered at doses of 0.3 μmol/kg and 3 μmol/kgi.t., respectively, did not show any significant effects on cellinfiltration and protein accumulation. The negative values obtained(trend: amplification of inflammation) fall into the range of biologicalvariability of the model and therefore, no significance must be attachedto these data.

[0033] In contrast, the long-acting β2-adrenergic receptor agonistSalmeterol given at a dose of 3 pmol/kg i.t exhibited inhibitory effectson total cell and eosinophil influx into alveolar space and proteinlevels in BAL fluid. However, the data failed to reach significance.

[0034] Co-administration of the PDE inhibitor Roflumilast orPumafentrine with Salmeterol resulted in synergistic effects compared toadministration of every compound alone, i.e. both PDE inhibitorscombined with the β2 agonist displayed a significant inhibition ofeosinophilia and reduction of protein concentration in the BAL fluid.The combination of the PDE3/4 inhibitor Pumafentrine and Salmeterol wasmore efficacious on all parameters measured (difference was notsignificant), and additionally, showed a significant effect oninhibition of total cell influx into the alveolar space.

1. A medicament comprising a PDE inhibitor, which is to be administeredorally, from the PDE4 or PDE3/4 inhibitors group combined with a β₂adrenoceptor agonist in fixed or free combination.
 2. The medicament asclaimed in claim 1, which is a fixed oral combination.
 3. The medicamentas claimed in claim 1 or 2 for use in the therapeutic treatment ofrespiratory tract disorders.
 4. The medicament as claimed in claim 1 or2, wherein the PDE inhibitor is a compound selected from the groupconsisting of arofylline, cipamfylline, D-4418, filaminast, ibudilast,laprafylline, ORG-20241, piclamilast, rolipram, SB-207499, tibenelastand V-11294A or a salt thereof.
 5. The medicament as claimed in claim 1or 2, wherein the PDE inhibitor is roflumilast, its salt and/or itsN-oxide.
 6. The medicament as claimed in claim 1 or 2, wherein the PDEinhibitor is BYK-33043, its salt and/or its N-oxide.
 7. The medicamentas claimed in claim 1 or 2, wherein the PDE inhibitor is roflumilast,its salt and/or its N-oxide and the β₂ adrenoceptor agonist issalmeterol or a salt thereof.
 8. The medicament as claimed in claim 1 or2, wherein the PDE inhibitor is BYK-33043, its salt and/or its N-oxideand the β₂ adrenoceptor agonist is salmeterol or a salt thereof.
 9. Themedicament as claimed in claim 1 or 2, wherein the β₂ adrenoceptoragonist is clenbuterol, orciprenaline, salbutamol, terbutaline,tulobuterol, bambuterol or reproterol or a salt thereof.
 10. Themedicament as claimed in claim 1 or 2, wherein the PDE inhibitor isarofylline, cipamfylline, D-4418, filaminast, ibudilast, laprafylline,ORG-20241, piclamilast, rolipram, SB-207499, tibenelast or V-11294A or asalt thereof, and the β₂ adrenoceptor agonist is clenbuterol,orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol orreproterol or a salt thereof.
 11. The medicament as claimed in claim 1or 2, wherein the PDE inhibitor is roflumilast or BYK-33043, their saltsand/or their N-oxides and the β₂ adrenoceptor agonist is clenbuterol,orciprenaline, salbutamol, terbutaline, tulobuterol, bambuterol orreproterol or a salt thereof.
 12. The use of a PDE inhibitor, which isto be administered orally, from the PDE4- or PDE3/4 inhibitors group inthe combined use with a β₂ adrenoceptor agonist in the therapeutictreatment of respiratory tract disorders.